Abstract Between 30-75% of cancer patients receiving adjuvant therapy experience a decline in cognitive ability termed Cancer-Related Cognitive Impairment (CRCI). These impairments include difficulty with memory and attention, which may impact day-to-day life and work performance. Up to 35% of cancer patients continue to experience CRCI for months to years after treatment completion, suggesting a long-term cognitive deficiency. Developing quantitative methods to detect the neural correlates of CRCI, and treatments to mitigate its symptoms will be imperative to improve cancer patients' quality of life. However, such advances will require a better understanding of the neural mechanisms underlying CRCI. Studies on CRCI have demonstrated objective cognitive impairments on neuropsychological exams in patients following cancer treatment. The most frequently impaired cognitive domains include memory, executive functioning, processing speed, and attention. Chemotherapy, hormone therapy and other cancer treatments are thought to impair cognitive functioning by altering specific brain structures and/or impairing connectivity between brain regions. The hippocampus and prefrontal cortex (PFC) are known to be integrally involved in memory and executive functioning, and are particularly sensitive to the effects of such treatments. Moreover, structural and functional imaging studies suggest that adjuvant cancer therapies target the structure of brain hub regions within in resting state networks, as well as overall resting state connectivity integrity. While evidence is clear for cognitive decline as well as structural and functional changes in patients treated with adjuvant therapies, the precise mechanism of impairment is poorly understood. Our preliminary findings revealed shape deformation on the surface of the hippocampus in breast cancer patients. Furthermore our group found that patients exhibit functional hypoactivation in the hippocampus on a task of covert memory, and hypoactivation of the dorsolateral prefrontal cortex on a task of working memory. The proposed study will test the hypothesis that impairments in hippocampal-PFC and other resting state networks involving the hippocampus contribute to cognitive deficits in CRCI. We will utilize multimodal imaging to examine how structural integrity of the components of the hippocampal-PFC network (Aim 1) and functional connectivity within this network (Aim 2) relate to specific cognitive measures. Finally, we will examine whether other regions and network connections, specifically within resting state networks, account for cognitive impairment (Aim 3). Results of this study will contribute to a deeper understanding of the neurobiology of CRCI. Further, this work may aid in the development of markers for cognitive impairment in this population and provide key anatomical targets for effective intervention.